jamaneurol.2020

Research
JAMA Neurology | Original Investigation
Neurologic Manifestations of Hospitalized Patients
With Coronavirus Disease 2019 in Wuhan, China
Ling Mao; Huijuan Jin; Mengdie Wang; Yu Hu; Shengcai Chen; Quanwei He; Jiang Chang; Candong Hong;
Yifan Zhou; David Wang; Xiaoping Miao; Yanan Li, MD, PhD; Bo Hu, MD, PhD
Editorial
IMPORTANCE The outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China,
Supplemental content
is serious and has the potential to become an epidemic worldwide. Several studies have
described typical clinical manifestations including fever, cough, diarrhea, and fatigue.
However, to our knowledge, it has not been reported that patients with COVID-19 had
any neurologic manifestations.
OBJECTIVE To study the neurologic manifestations of patients with COVID-19.
DESIGN, SETTING, AND PARTICIPANTS This is a retrospective, observational case series. Data
were collected from January 16, 2020, to February 19, 2020, at 3 designated special care
centers for COVID-19 (Main District, West Branch, and Tumor Center) of the Union Hospital
of Huazhong University of Science and Technology in Wuhan, China. The study included
214 consecutive hospitalized patients with laboratory-confirmed diagnosis of severe acute
respiratory syndrome coronavirus 2 infection.
MAIN OUTCOMES AND MEASURES Clinical data were extracted from electronic medical
records, and data of all neurologic symptoms were checked by 2 trained neurologists.
Neurologic manifestations fell into 3 categories: central nervous system manifestations
(dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and
seizure), peripheral nervous system manifestations (taste impairment, smell impairment,
vision impairment, and nerve pain), and skeletal muscular injury manifestations.
RESULTS Of 214 patients (mean [SD] age, 52.7 [15.5] years; 87 men [40.7%]) with COVID-19,
126 patients (58.9%) had nonsevere infection and 88 patients (41.1%) had severe infection
according to their respiratory status. Overall, 78 patients (36.4%) had neurologic
manifestations. Compared with patients with nonsevere infection, patients with severe
infection were older, had more underlying disorders, especially hypertension, and showed
fewer typical symptoms of COVID-19, such as fever and cough. Patients with more severe
infection had neurologic manifestations, such as acute cerebrovascular diseases (5 [5.7%]
vs 1 [0.8%]), impaired consciousness (13 [14.8%] vs 3 [2.4%]), and skeletal muscle injury
(17 [19.3%] vs 6 [4.8%]).
CONCLUSIONS AND RELEVANCE Patients with COVID-19 commonly have neurologic
manifestations. During the epidemic period of COVID-19, when seeing patients with
neurologic manifestations, clinicians should suspect severe acute respiratory syndrome
coronavirus 2 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis
and lose the chance to treat and prevent further transmission.
Author Affiliations: Author
affiliations are listed at the end of this
article.
JAMA Neurol. doi:10.1001/jamaneurol.2020.1127
Published online April 10, 2020.
Corresponding Authors: Bo Hu, MD,
PhD ([email protected]) and
Yanan Li, MD, PhD ([email protected].
edu.cn), Department of Neurology,
Union Hospital, Tongji Medical
College, Huazhong University of
Science and Technology, Wuhan,
430022, China.
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Research Original Investigation
Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China
I
n December 2019, many unexplained pneumonia cases
occurred in Wuhan, China, and rapidly spread to other parts
of China, then to Europe, North America, and Asia. This
outbreak was confirmed to be caused by a novel coronavirus
(CoV).1 The novel CoV was reported to have symptoms resembling that of severe acute respiratory syndrome CoV (SARSCoV) in 2003.2 Both shared the same receptor, angiotensinconverting enzyme 2 (ACE2).3 Therefore, this virus was named
SARS-CoV-2, and in February 2020, the World Health Organization (WHO) named the disease coronavirus disease 2019
(COVID-19). As of March 5, 2020, there were 95 333 confirmed cases of COVID-19 and 3282 deaths globally.4
Coronaviruses can cause multiple systemic infections or
injuries in various animals.5 The CoVs can adapt quickly and
cross the species barrier, such as with SARS-CoV and Middle
East respiratory syndrome CoV (MERS-CoV), causing epidemics or pandemics. Infection in humans often leads to severe
clinical symptoms and high mortality.6 As for COVID-19, several studies have described typical clinical manifestations
including fever, cough, diarrhea, and fatigue. Coronavirus
disease 2019 also has characteristic laboratory findings and
lung computed tomography (CT) abnormalities.7 However, to
our knowledge, it has not been reported that patients with
COVID-19 had any neurologic manifestations. Here, we report the characteristic neurologic manifestations of SARSCoV-2 infection in 78 of 214 patients with laboratoryconfirmed diagnosis of COVID-19 and treated at our hospitals,
which are located in the epicenter of Wuhan.
Methods
Study Design and Participants
This retrospective, observational study was done at 3 centers
(Main District, West Branch, and Tumor Center) of Union Hospital of Huazhong University of Science and Technology
(Wuhan, China). These 3 centers are designated hospitals assigned by the government to treat patients with COVID-19. We
retrospectively analyzed consecutive patients from January 16,
2020, to February 19, 2020, who had been diagnosed as having COVID-19, according to WHO interim guidance.8 A confirmed case of COVID-19 was defined as a positive result on highthroughput sequencing or real-time reverse-transcription
polymerase chain reaction analysis of throat swab specimens.
Throat swab samples were collected and placed into a collection tube containing preservation solution for the virus.9 A
SARS-CoV-2 infection was confirmed by real-time reversetranscription polymerase chain reaction assay using a SARSCoV-2 nucleic acid detection kit according to the manufacturer’s protocol (Shanghai bio-germ Medical Technology Co).
Radiologic assessments included chest and head CT, and all laboratory testing (a complete blood cell count, blood chemical
analysis, coagulation testing, assessment of liver and renal function testing, C-reactive protein, creatine kinase, and lactate dehydrogenase) was performed according to the clinical care needs
of the patient. Two hundred fourteen hospitalized patients with
laboratory confirmation of SARS-CoV-2 were included in the
analysis.9 Before enrollment, verbal consent was obtained from
E2
Key Points
Question What are neurologic manifestations of patients with
coronavirus disease 2019?
Findings In a case series of 214 patients with coronavirus disease
2019, neurologic symptoms were seen in 36.4% of patients and
were more common in patients with severe infection (45.5%)
according to their respiratory status, which included acute
cerebrovascular events, impaired consciousness, and muscle
injury.
Meaning Neurologic symptoms manifest in a notable proportion
of patients with coronavirus disease 2019.
patients or an accompanying relative for patients who could not
give consent. The study was performed in accordance with the
principles of the Declaration of Helsinki. This study was approved and written informed consent was waived by the
Ethics Committee of Union hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China,
on February 20, 2020, owing to the rapid emergence of the
disease and the urgent need to collect data.
Data Collection
We reviewed electronic medical records, nursing records, laboratory findings, and radiologic examinations for all patients
with laboratory-confirmed SARS-CoV-2 infection and collected data on age, sex, comorbidities (hypertension, diabetes, cardiac or cerebrovascular disease, malignancy, and chronic
kidney disease), typical symptoms from onset to hospital admission (fever, cough, anorexia, diarrhea, throat pain, abdominal pain), nervous system symptoms, laboratory findings, and
CT scan (chest and head if available). Subjective symptoms
were provided by patients who were conscious, cognitively and
mentally normal, and linguistically competent to respond to
interview. Any missing or uncertain records were collected and
clarified through direct communication with involved patients, health care clinicians, and their families. We defined the
degree of severity of COVID-19 (severe vs nonsevere) at the time
of admission using the American Thoracic Society guidelines
for community-acquired pneumonia.10
All neurologic manifestations were reviewed and confirmed by 2 trained neurologists. Major disagreement between 2 reviewers was resolved by consultation with a third
reviewer. Neurologic manifestations were categorized into
3 categories: central nervous system (CNS) manifestations
(dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and seizure), peripheral nervous system (PNS) manifestations (taste impairment, smell impairment, vision impairment, and nerve pain), and skeletal
muscular injury manifestations. Impaired consciousness includes the change of consciousness level (somnolence, stupor, and coma) and consciousness content (confusion and
delirium). To avoid cross-infection during the outbreak, we
had to minimize patients going out for examination. Therefore, the diagnosis of nervous system manifestations mainly
depended on the subjective symptoms of patients and the
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Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China
examinations available. Acute cerebrovascular disease includes ischemic stroke and cerebral hemorrhage diagnosed by
clinical symptoms and head CT. Seizure is based on the clinical symptoms at the time of presentation. Skeletal muscle injury was defined as when a patient had skeletal muscle pain
and elevated serum creatine kinase level greater than 200 U/L
(to convert to microkatals per liter, multiply by 0.0167).7
Statistical Analysis
For baseline data, mean and standard deviations (SD) were used
for normally distributed data and median and range for data
that were not normally distributed. Categorical variables were
expressed as counts and percentages. Continuous variables
were compared by using the Wilcoxon rank sum test. Proportions for categorical variables were compared using the χ2 test.
All statistical analyses were performed using R, version 3.3.0,
software (the R Foundation). The significance threshold was
set at a 2-sided P value less than .05.
Results
Demographic and Clinical Characteristics
A total of 214 hospitalized patients with confirmed SARSCoV-2 infection were included in the analysis. Their demographic and clinical characteristics were shown in Table 1. Their
mean (SD) age was 52.7 (15.5) years, and 87 were men (40.7%).
Of these patients, 83 (38.8%) had at least 1 of the following
underlying disorders: hypertension (51 [23.8%]), diabetes
(30 [14.0%]), cardiac or cerebrovascular disease (15 [7.0%]),
and malignancy (13 [6.1%]). The most common symptoms at
onset of illness were fever (132 [61.7%]), cough (107 [50.0%]),
and anorexia (68 [31.8%]). Seventy-eight patients (36.4%) had
nervous system manifestations: CNS (53 [24.8%]), PNS (19
[8.9%]), and skeletal muscle injury (23 [10.7%]). In patients with
CNS manifestations, the most common reported symptoms
were dizziness (36 [16.8%]) and headache (28 [13.1%]). In patients with PNS symptoms, the most common reported symptoms were taste impairment (12 [5.6%]) and smell impairment (11 [5.1%]).
According to the American Thoracic Society guidelines for
community-acquired pneumonia,10 88 patients (41.1%) had
severe infection and 126 patients (58.9%) had nonsevere infection. The patients with severe infection were significantly
older (mean [SD] age, 58.2 [15.0] years vs 48.9 [14.7] years;
P < .001) and more likely to have other underlying disorders
(42 [47.7%] vs 41 [32.5%]; P = .03), especially hypertension (32
[36.4%] vs 19 [15.1%]; P < .001), and had fewer typical symptoms of COVID-19 such as fever (40 [45.5%] vs 92 [73%];
P < .001) and dry cough (30 [34.1%] vs 77 [61.1%]; P < .001).
Moreover, nervous system manifestations were significantly
more common in severe infections compared with nonsevere infections (40 [45.5%] vs 38 [30.2%], P =n .02). They included acute cerebrovascular disease (5 [5.7%]; 4 patients with
ischemic stroke and 1 with cerebral hemorrhage who died later
of respiratory failure; vs 1 [0.8%]; 1 patient with ischemic stroke;
P = .03, Figure), impaired consciousness (13 [14.8%] vs 3 [2.4%];
P < .001), and skeletal muscle injury (17 [19.3%] vs 6 [4.8%];
jamaneurology.com
Original Investigation Research
P < .001). In the severe group, 1 patient had a seizure characterized by a sudden onset of limb twitching, foaming in the
mouth, and loss of consciousness, which lasted for 3 minutes.
Apart from cerebrovascular disease and impaired consciousness, most neurologic manifestations occurred early in
the illness (median time, 1-2 days). Of 6 patients with acute
cerebrovascular disease, 2 arrived at the emergency department owing to sudden onset of hemiplegia but without any
typical symptoms (fever, cough, anorexia, and diarrhea) of
COVID-19. Their lung lesions were found by an emergent lung
CT and were diagnosed as having COVID-19 by a positive SARSCoV-2 nucleic acid detection in the later stage. Some patients
with fever and headache were admitted to the neurology ward
after initially being ruled out of COVID-19 by routine blood test
results and a screening lung CT in the clinic. However, several days later, they had typical COVID-19 symptoms such as
cough, throat pain, lower lymphocyte count, and groundglass opacity appearance on lung CT. Their diagnosis of
COVID-19 was confirmed by a positive nucleic acid test and then
they were transferred to the isolation ward.
Laboratory Findings in Patients
and With Severe and Nonsevere Infection
Table 2 showed the laboratory findings in severe and nonsevere subgroups. Patients with severe infection had more increased inflammatory response, including higher white blood
cell counts, neutrophil counts, lower lymphocyte counts,
and increased C-reactive protein levels compared with those
patients with nonsevere infection (white blood cell count:
median, 5.4 × 109/L [range, 0.1-20.4] vs 4.5 × 109/L [range,
1.8-14.0]; P < .001; neutrophil: median, 3.8 × 109/L [range,
0.0-18.7] vs 2.6 × 109/L [range, 0.7-11.8]; P < .001; lymphocyte count: median, 0.9 × 109/L [range, 0.1-2.6] vs 1.3 × 109/L
[range, 0.4-2.6]; P < .001; C-reactive protein: median, 37.1 mg/L
[range, 0.1-212.0] vs 9.4 mg/L [range, 0.2-126.0]; P < .001). The
patients with severe infection had higher D-dimer levels
than patients with nonsevere infection (median, 0.9 mg/L
[range, 0.1-20.0] vs 0.4 mg/L [range, 0.2-8.7]; P < .001), which
was indicative of consumptive coagulation system. In addition, patients with severe infection had multiple organ
involvement, such as serious liver (increased lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase levels), kidney (increased blood urea nitrogen and creatinine levels), and skeletal muscle damage (increased
creatinine kinase levels).
Laboratory Findings in Patients
With and Without CNS Symptoms
Table 3 showed the laboratory findings of patients with and
without CNS symptoms. We found that patients with CNS
symptoms had lower lymphocyte levels, platelet counts, and
higher blood urea nitrogen levels compared with those without CNS symptoms (lymphocyte count: median, 1.0 × 109/L
[range, 0.1-2.3] vs 1.2 × 109/L [range, 0.2-2.6], P = .049; platelet count: median, 180.0 × 109/L [range, 18.0-564.0] vs 227.0
× 109/L [range, 42.0-583.0], P = .005; blood urea nitrogen: median, 4.5 mmol/L [range, 1.6-48.1] vs 4.1 mmol/L [range, 1.519.1], P = .04). For the severe subgroup, patients with CNS
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Research Original Investigation
Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China
Table 1. Clinical Characteristics of Patients With COVID-19
No. (%)
Total
(N = 214)
52.7 (15.5)
Severe
(n = 88)
58.2 (15.0)
Nonsevere
(n = 126)
48.9 (14.7)
<50
90 (42.1)
24 (27.3)
66 (52.4)
≥50
124 (57.9)
64 (72.7)
60 (47.6)
Characteristic
Age, mean (SD), y
P valuea
Age, y
<.001
Sex
Female
127 (59.3)
44 (50.0)
83 (65.9)
Male
87 (40.7)
44 (50.0)
43 (34.1)
Any
83 (38.8)
42 (47.7)
41 (32.5)
.03
Hypertension
51 (23.8)
32 (36.4)
19 (15.1)
<.001
Diabetes
30 (14.0)
15 (17.0)
15 (11.9)
.29
Cardiac or cerebrovascular disease
15 (7.0)
7 (8.0)
8 (6.3)
.65
Malignancy
13 (6.1)
5 (5.7)
8 (6.3)
.84
Chronic kidney disease
6 (2.8)
2 (2.3)
4 (3.2)
.69
.02
Comorbidities
Typical symptoms
Fever
132 (61.7)
40 (45.5)
92 (73.0)
<.001
Cough
107 (50.0)
30 (34.1)
77 (61.1)
<.001
Anorexia
68 (31.8)
21 (23.9)
47 (37.3)
.04
Diarrhea
41 (19.2)
13 (14.8)
28 (22.2)
.17
Throat pain
31 (14.5)
10 (11.4)
21 (16.7)
.28
Abdominal pain
10 (4.7)
6 (6.8)
4 (3.2)
.21
Any
78 (36.4)
40 (45.5)
38 (30.2)
.02
CNS
53 (24.8)
27 (30.7)
26 (20.6)
.09
Dizziness
36 (16.8)
17 (19.3)
19 (15.1)
.42
Headache
28 (13.1)
15 (17.0)
13 (10.3)
.15
Impaired consciousness
16 (7.5)
13 (14.8)
3 (2.4)
<.001
Acute cerebrovascular disease
6 (2.8)
5 (5.7)
1 (0.8)
.03
Ataxia
1 (0.5)
1 (1.1)
0
NA
Seizure
1 (0.5)
1 (1.1)
0
NA
PNS
19 (8.9)
7 (8.0)
12 (9.5)
.69
Taste
12 (5.6)
3 (3.4)
9 (7.1)
.24
Smell
11 (5.1)
3 (3.4)
8 (6.3)
.34
Vision
3 (1.4)
2 (2.3)
1 (0.8)
.37
Nerve pain
5 (2.3)
4 (4.5)
1 (0.8)
.07
23 (10.7)
17 (19.3)
6 (4.8)
<.001
Dizziness
1 (1-30)
1 (1-30)
1 (1-14)
NA
Headache
1 (1-14)
1 (1-3)
3 (1-14)
NA
Impaired consciousness
8 (1-25)
10 (1-25)
1 (1-3)
NA
Acute cerebrovascular disease
9 (1-18)
10 (1-18)
1 (1)
NA
Ataxia
2 (2)
2 (2)
NA
NA
Seizure
2 (2)
2 (2)
NA
NA
Nervous system symptoms
Impairment
Skeletal muscle injury
Onset of symptoms to hospital
admission, median (range), d
CNS
PNS
Impairment
Taste
2 (1-5)
3 (1-3)
2 (1-5)
NA
Smell
2 (1-5)
1 (1-4)
2 (1-5)
NA
Vision
2 (1-3)
3 (2-3)
1 (1)
NA
Nerve pain
1 (1-1)
1 (1-1)
1 (1)
NA
1 (1-11)
1 (1-11)
1 (1-6)
NA
Skeletal muscle injury
E4
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Abbreviations: CNS, central nervous
system; COVID-19, coronavirus
disease 2019; NA, not applicable;
PNS, peripheral nervous system.
a
P values indicate differences
between patients with severe and
nonsevere infection, and P less than
.05 was considered statistically
significant.
jamaneurology.com
Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China
Original Investigation Research
Figure. Representative Computed Tomography (CT) Images of a Patient With Coronavirus Disease 2019
With New Onset of Ischemic Stroke
A Brain computed tomography
B
Chest computed tomography
A, Brain CT image 1 day after ischemic
stroke. White arrowhead indicates
the ischemic lesion. B, Chest CT
image 1 day after ischemic stroke.
Table 2. Laboratory Findings of Patients With COVID-19
Median (range)
Total
(N = 214)
Severe
(n = 88)
Nonsevere
(n = 126)
P valuea
White blood cell
4.9 (0.1-20.4)
5.4 (0.1-20.4)
4.5 (1.8-14.0)
.008
Neutrophil
3.0 (0.0-18.7)
3.8 (0.0-18.7)
2.6 (0.7-11.8)
<.001
Lymphocyte
1.1 (0.1-2.6)
0.9 (0.1-2.6)
1.3 (0.4-2.6)
<.001
Platelet
209.0 (18.0-583.0)
204.5 (18.0-576.0)
219.0 (42.0-583.0)
.25
Laboratory finding
Count, ×109/L
C-reactive protein, mg/L
12.2 (0.1-212.0)
37.1 (0.1-212.0)
9.4 (0.4-126.0)
<.001
D-dimer, mg/L
0.5 (0.1-20.0)
0.9 (0.1-20.0)
0.4 (0.2-8.7)
<.001
Creatine kinase, U/L
64.0 (8.8-12216.0)
83.0 (8.8-12216.0)
59.0 (19.0-1260.0)
.004
Lactate dehydrogenase, U/L
241.5 (2.2-908.0)
302.0 (2.2-880.0)
215.0 (2.5-908.0)
<.001
Alanine
26.0 (5.0-1933.0)
32.5 (5.0-1933.0)
23.0 (6.0-261.0)
.04
Aspartate
26.0 (8.0-8191.0)
34.0 (8.0-8191.0)
23.0 (9.0-244.0)
<.001
Blood urea nitrogen, mmol/L
4.1 (1.5-48.1)
4.6 (1.5-48.1)
3.8 (1.6-13.7)
<.001
Creatinine, μmol/L
68.2 (35.9-9435.0)
71.6 (35.9-9435.0)
65.6 (39.4-229.1)
.03
Aminotransferase, U/L
Abbreviation: COVID-19, coronavirus
disease 2019.
SI conversion factor: To convert
aminotransferase levels to
microkatals per liter, multiply by
0.0167; creatine kinase to microkatals
per liter, multiply by 0.0167; lactate
dehydrogenase to microkatals per
liter, multiply by 0.0167.
a
symptoms also had lower lymphocyte levels and platelet
counts and higher blood urea nitrogen levels compared with
those without CNS symptoms (lymphocyte count: median, 0.7
× 109/L [range, 0.1-1.6] vs 0.9 × 109/L [range, 0.2-2.6], P = .007;
platelet count: median, 169.0 × 109/L [range, 18.0-564.0] vs
220.0 × 109/L [range, 109.0-576.0], P = .04; blood urea nitrogen: median, 5.0 mmol/L [range, 2.3-48.1] vs 4.4 mmol/L
[range, 1.5-19.1], P = .04). For the nonsevere subgroup, there
were no significant differences in laboratory findings of patients with and without CNS symptoms.
Laboratory Findings in Patients
With and Without PNS Symptoms
Table 4 showed the laboratory findings of patients with and
without PNS symptoms. We found that there were no significant differences in laboratory findings of patients with PNS and
those without PNS. Similar results were also found in the severe subgroup and nonsevere subgroup, respectively.
jamaneurology.com
P values indicate differences
between patients with severe and
nonsevere infection, and P less than
.05 was considered statistically
significant.
Laboratory Findings in Patients
With and Without Skeletal Muscle Injury
The eTable in the Supplement shows the laboratory findings
of patients with and without skeletal muscle injury. Compared with the patients without muscle injury, patients with
muscle injury had significantly higher levels of creatine kinase (median, 400.0 U/L [range 203.0-12216.0] vs median, 58.5
U/L [range 8.8-212.0]; P < .001), regardless of their severity.
Meanwhile, patients with muscle injury had higher neutrophil counts, lower lymphocyte counts, higher C-reactive protein levels, and higher D-dimer levels. The abnormalities were
manifestations of increased inflammatory response and blood
coagulation function. In addition, we found that patients with
muscle injury had multiorgan damage, including more serious liver (increased lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase levels) and kidney (increased blood urea nitrogen and creatinine levels)
abnormalities.
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Research Original Investigation
Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China
Table 3. Laboratory Findings of Patients With COVID-19 With CNS Symptomsa
Median (range)
Total
Laboratory finding
With CNS
symptoms
(n = 53)
Severe
Without CNS
symptoms
(n = 161)
P
value
Nonsevere
With CNS
symptoms
(n = 27)
Without CNS
symptoms
(n = 61)
P
value
With CNS
symptoms
(n = 26)
Without CNS
symptoms
(n = 100)
P
value
Count, ×109/L
White blood cell
4.6 (0.1-12.5) 4.9 (1.8-20.4) .58
5.3 (0.1-12.5)
5.5 (1.9-20.4)
.77
4.1 (2.4-11.0) 4.6 (1.8-14.0)
Neutrophil
2.6 (0.0-10.9) 3.1 (0.7-18.7) .41
3.8 (0.0-10.9)
3.6 (0.7-18.7)
>.99
2.2 (0.9-7.4)
2.8 (0.7-11.8)
.40
.11
Lymphocyte
1.0 (0.1-2.3)
1.2 (0.2-2.6)
.049
0.7 (0.1-1.6)
0.9 (0.2-2.6)
.007
1.3 (0.7-2.3)
1.3 (0.4-2.6)
.49
Platelet
180.0
(18.0-564.0)
227.0
(42.0-583.0)
.005
169.0
(18.0-564.0)
220.0
(109.0-576.0)
.04
188.5
232.0
(110.0-548.0) (42.0-583.0)
.09
C-reactive protein,
mg/L
14.1
(0.1-212.0)
11.4
(0.1-204.5)
.31
48.6
(0.1-212.0)
26.1
(0.1-204.5)
.68
7.4
(3.1-111.0)
9.8 (0.4-126.0)
.82
D-dimer, mg/L
0.5 (0.2-9.7)
0.5 (0.1-20.0) .75
1.2 (0.2-9.7)
0.9 (0.1-20.0)
.42
0.4 (0.2-6.4)
0.4 (0.2-8.7)
.46
Creatine kinase, U/L
79.0
60.5
.17
(8.8-12216.0) (19.0-1260.0)
104.0
(8.8-12 216.0)
64.0
(19.0-1214.0)
.08
52.5
(28.0-206.0)
59.0
(19.0-1260.0)
.56
Lactate
dehydrogenase, U/L
243.0
(2.2-880.0)
241.0
(3.5-908.0)
.77
334.0
(2.2-880.0)
299.0
(3.5-743.0)
.32
198.0
(2.5-417.0)
226.0
(121.0-908.0)
.14
Alanine
27.0
(5.0-261.0)
26.0
(6.0-1933.0)
.21
35.0
(5.0-259.0)
31.0
(7.0-1933.0)
.32
25.5
(13.0-261.0)
23.0
(6.0-135.0)
.68
Aspartate
29.5
(13.0-213.0)
26.0
(8.0-8191.0)
.10
35.5
(14.0-213.0)
34.0
(8.0-8191.0)
.32
23.0
(13.0-198.0)
23.5
(9.0-244.0)
.56
Aminotransferase, U/L
Blood urea nitrogen,
mmol/L
4.5 (1.6-48.1) 4.1 (1.5-19.1) .04
5.0 (2.3-48.1)
4.4 (1.5-19.1)
.04
3.9 (1.6-9.4)
3.8 (1.7-13.7)
.57
Creatinine, μmol/L
71.7
66.3
.06
(37.1-1299.2) (35.9-9435.0)
71.7
(37.1-1299.2)
68.4
(35.9-9435.0)
.25
72.0
(40.3-133.6)
63.4
(39.4-229.1)
.27
Abbreviations: CNS, central nervous system; COVID-19, coronavirus disease
2019.
SI conversion factor: To convert aminotransferase levels to microkatals per liter,
multiply by 0.0167; creatine kinase to microkatals per liter, multiply by 0.0167;
For the severe group, patients with skeletal muscle injury
had decreased lymphocyte counts and more serious liver
injury (increased lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase levels) and kidney injury (increased creatinine levels).
Discussion
To our knowledge, this is the first report on detailed neurologic manifestations of the hospitalized patients with COVID19. As of February 19, 2020, of 214 patients included in this
study, 88 (41.1%) had severe infection and 126 (58.9%) had nonsevere infection. Of these, 78 (36.4%) had various neurologic
manifestations that involved CNS, PNS, and skeletal muscles.
Compared with patients with nonsevere infection, patients
with severe infection were older and had more hypertension
but fewer typical symptoms such as fever and cough. Patients with severe infection were more likely to develop neurologic manifestations, especially acute cerebrovascular disease, conscious disturbance, and skeletal muscle injury. Most
neurologic manifestations occurred early in the illness (the
median time to hospital admission was 1-2 days). Some patients without typical symptoms (fever, cough, anorexia, and
diarrhea) of COVID-19 came to the hospital with only neurologic manifestation as their presenting symptoms. Therefore, for patients with COVID-19, we need to pay close attention to their neurologic manifestations, especially for those
E6
lactate dehydrogenase to microkatals per liter, multiply by 0.0167.
a
P values indicate differences between patients with and without CNS
symptoms, and P less than .05 was considered statistically significant.
with severe infections, which may have contributed to their
death. Moreover, during the epidemic period of COVID-19,
when seeing patients with these neurologic manifestations,
physicians should consider SARS-CoV-2 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and
prevention of transmission.
In January 2020,3 ACE2 was identified as the functional
receptor for SARS-CoV-2, which is present in multiple human
organs, including nervous system and skeletal muscles.11 The
expression and distribution of ACE2 remind us that the SARSCoV-2 may cause some neurologic manifestations through direct or indirect mechanisms. Autopsy results of patients with
COVID-19 showed that the brain tissue was hyperemic and
edematous and some neurons degenerated.12 Neurologic injury has been confirmed in the infection of other CoVs such
as in SARS-CoV and MERS-CoV. The researchers detected SARSCoV nucleic acid in the cerebrospinal fluid of those patients
and also in their brain tissue on autopsy.13,14
Central nervous system symptoms were the main form of
neurologic injury in patients with COVID-19 in this study. The
pathologic mechanism may be from the CNS invasion of SARSCoV-2, similar to SARS and MERS viruses. As with other respiratory viruses, SARS-COV-2 may enter the CNS through the
hematogenous or retrograde neuronal route. The latter can be
supported by the fact that some patients in this study had smell
impairment. We also found that the lymphocyte counts were
lower for patients with CNS symptoms than without CNS symptoms. This phenomenon may be indicative of the immuno-
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Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China
Original Investigation Research
Table 4. Laboratory Findings of Patients With COVID-19 With PNS Symptoms
Median (range)
Total
Severe
Nonsevere
With PNS
symptoms
(n = 12)
Without PNS
symptoms
(n = 114)
P value
5.6 (0.1-20.4) .11
4.9 (2.8-7.5)
4.4 (1.8-14.0)
.27
4.1 (0.0-18.7) .10
2.9 (1.9-5.4)
2.5 (0.7-11.8)
.21
0.9 (0.1-2.6)
.26
1.2 (0.7-2.6)
1.3 (0.4-2.4)
.92
.56
204.0
205.0
(111.0-245.0) (18.0-576.0)
.56
214.5
219.0
(155.0-305.0) (42.0-583.0)
.81
.45
7.5 (3.1-76.4) 43.7
(0.1-212.0)
.13
13.0
(3.1-81.0)
8.8
(0.4-126.0)
.60
1.3 (0.1-20.0) .27
0.4 (0.2-4.5)
0.4 (0.2-8.7)
.99
105.0
83.0
.76
(32.0-1214.0) (8.8-12216.0)
66.0
(42.0-171.0)
57.5
(19.0-1260.0)
.29
.05
254.0
(2.5-481.0)
215.0
(2.9-908.0)
.67
.23
26.0
(8.0-116.0)
23.0
(6.0-261.0)
.56
35.5
.13
(12.0-8191.0)
22.0
(14.0-115.0)
23.5
(9.0-244.0)
>.99
4.2 (3.5-8.8)
4.7 (1.5-48.1) .96
3.7 (1.6-5.3)
3.9 (1.7-13.7)
.66
71.4
(58.3-121.4)
71.7
.72
(35.9-9435.0)
59.9
(48.1-77.3)
66.6
(39.4-229.1)
.24
With PNS
symptoms
(n = 7)
Without PNS
symptoms
(n = 81)
4.9 (0.1-20.4) .74
4.5 (3.1-6.8)
3.0 (0.0-18.7) .74
2.6 (1.5-5.3)
1.1 (0.1-2.6)
.43
1.2 (0.6-1.6)
204.0
213.0
(111.0-305.0) (18.0-583.0)
C-reactive protein,
mg/L
12.0
(3.1-81.0)
12.3
(0.1-212.0)
D-dimer, mg/L
0.4 (0.2-9.5)
0.5 (0.1-20.0) .40
Creatine kinase, U/L
67.0
64.0
.41
(32.0-1214.0) (8.8-12216.0)
Lactate
dehydrogenase, U/L
205.0
(2.5-517.0)
242.0
(2.2-908.0)
.28
170.0
(46.0-517.0)
309.0
(2.2-880.0)
Alanine
26.0
(5.0-116.0)
27.0
(6.0-1933.0)
.70
19.0
(5.0-80.0)
35.0
(8.0-1933.0)
Aspartate
22.0
(8.0-115.0)
27.0
(9.0-8191.0)
.29
22.0
(8.0-53.0)
Blood urea nitrogen,
mmol/L
4.1 (1.6-8.8)
4.1 (1.5-48.1) .76
Creatinine, μmol/L
62.5
(48.1-121.4)
68.3
.46
(35.9-9435.0)
With PNS
symptoms
(n = 19)
Without PNS
symptoms
(n = 195)
White blood cell
4.8 (2.8-7.5)
Neutrophil
2.8 (1.5-5.4)
Lymphocyte
1.2 (0.6-2.6)
Platelet
Laboratory finding
P value
P value
Count, ×109/L
0.5 (0.2-9.5)
Aminotransferase, U/L
Abbreviations: COVID-19, coronavirus disease 2019; PNS, peripheral nervous
system.
SI conversion factor: To convert aminotransferase levels to microkatals per liter,
multiply by 0.0167; creatine kinase to microkatals per liter, multiply by 0.0167;
suppression in patients with COVID-19 with CNS symptoms,
especially in the severe subgroup. Moreover, we found patients with severe infection had higher D-dimer levels than that
of patients with nonsevere infection. This may be the reason
why patients with severe infection are more likely to develop
cerebrovascular disease.
Consistent with the previous studies,7 muscle symptoms
were also common in our study. We speculate that the symptom was owing to skeletal muscle injury, as confirmed by
elevated creatine kinase levels. We found that patients with
muscle symptoms had higher creatine kinase and lactate
dehydrogenase levels than those without muscle symptoms.
Furthermore, creatine kinase and lactate dehydrogenase levels in patients with severe infection were much higher than
those of patients with nonsevere infection. This injury could
be associated with ACE2 in skeletal muscle. 15 However,
SARS-CoV, using the same receptor, was not detected in
skeletal muscle by postmortem examination.16 Therefore,
whether SARS-CoV-2 infects skeletal muscle cells by binding
with ACE2 needs to be further studied. One other reason was
the infection-mediated harmful immune response that
caused the nervous system abnormalities. Significantly
elevated proinflammatory cytokines in serum may cause
skeletal muscle damage.
Limitations
This study has several limitations. First, only 214 patients were
studied, which could cause biases in clinical observation. It
jamaneurology.com
lactate dehydrogenase to microkatals per liter, multiply by 0.0167.
a
P values indicate differences between patients with and without PNS
symptoms, and P less than .05 was considered statistically significant.
would be better to include more patients from Wuhan, other
cities in China, and even other countries. Second, all data were
abstracted from the electronic medical records; certain patients with neurologic symptoms might not be captured if their
neurologic manifestations were too mild, such as with taste
impairment and smell impairment. Third, because most patients were still hospitalized and information regarding clinical outcomes was unavailable at the time of analysis, it was
difficult to assess the effect of these neurologic manifestations on their outcome, and continued observations of the
natural history of disease are needed. Fourth, during the outbreak period of COVID-19, because of the influx of many patients infected with SARS-CoV-2, advanced neuroimaging, such
as magnetic resonance imaging and diagnostic procedures such
as lumbar puncture and electromyography/nerve conduction velocity, was purposefully avoided to reduce the risk of
cross infection. Therefore, in our study, most of the symptoms were a patient’s subjective descriptions. We could not
distinguish whether these neurologic manifestations are
caused by the virus directly or by the pulmonary disease or
other organ damage indirectly.
Conclusions
In conclusion, SARS-CoV-2 may infect nervous system and
skeletal muscle as well as the respiratory tract. In those with
severe infection, neurologic involvement is greater, which
(Reprinted) JAMA Neurology Published online April 10, 2020
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E7
Research Original Investigation
Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China
includes acute cerebrovascular diseases, impaired consciousness, and skeletal muscle injury. Their clinical conditions may
worsen, and patients may die sooner. This study may offer important new clinical information on COVID-19 that would help
clinicians raise awareness of its involvement of neurologic
manifestations. It is especially meaningful to learn that for
those with severe COVID-19, rapid clinical deterioration or
Refractory Diseases Pilot Project of Clinical
Collaboration with Chinese and Western Medicine
(SATCM-20180339).
ARTICLE INFORMATION
Accepted for Publication: March 26, 2020.
Published Online: April 10, 2020.
doi:10.1001/jamaneurol.2020.1127
Author Affiliations: Department of Neurology,
Union Hospital, Tongji Medical College, Huazhong
University of Science and Technology, Wuhan,
China (Mao, Jin, M. Wang, Chen, He, Hong, Zhou, Li,
B. Hu); Department of Hematology, Union Hospital,
Tongji Medical College, Huazhong University of
Science and Technology, Wuhan, China (Y. Hu);
Department of Epidemiology and Biostatistics,
Key Laboratory for Environment and Health,
School of Public Health, Tongji Medical College,
Huazhong University of Science and Technology,
Wuhan, China (Chang, Miao); Neurovascular
Division, Department of Neurology, Barrow
Neurological Institute, Saint Joseph’s Hospital and
Medical Center, Phoenix, Arizona (D. Wang).
Author Contributions: Dr B. Hu had full access to
all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis. Drs Mao, Jin, M. Wang, Y. Hu, Chen,
He, and Chang contributed equally and share first
authorship.
Concept and design: Mao, Jin, Y. Hu, He, Miao,
B. Hu.
Acquisition, analysis, or interpretation of data:
Mao, Jin, M. Wang, Chen, Chang, Hong, Zhou,
D. Wang, Li.
Drafting of the manuscript: Mao, Jin, M. Wang,
Chen, Chang, Zhou, D. Wang, B. Hu.
Critical revision of the manuscript for important
intellectual content: Y. Hu, He, Hong, D. Wang, Miao,
Li, B. Hu.
Statistical analysis: Chang.
Obtained funding: Mao, B. Hu.
Administrative, technical, or material support: Mao,
Jin, M. Wang, Chen, He, Zhou, D. Wang, Miao, Li,
B. Hu.
Supervision: Y. Hu, B. Hu.
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was supported by
the National Key Research and Development
Program of China (2018YFC1312200 to Dr B. Hu),
the National Natural Science Foundation of China
(81820108010 to Dr B. Hu, No.81974182 to
Dr Mao and 81671147 to Dr Jin)and Major
E8
worsening could be associated with a neurologic event such
as stroke, which would contribute to its high mortality rate.
Moreover, during the epidemic period of COVID-19, when seeing patients with these neurologic manifestations, clinicians
should consider SARS-CoV-2 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and prevention of transmission.
Role of the Funder/Sponsor: The funding
sourceshad no role in the design and conduct of
the study; collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
REFERENCES
1. Zhu N, Zhang D, Wang W, et al; China Novel
Coronavirus Investigating and Research Team.
A novel coronavirus from patients with pneumonia
in China. N Engl J Med. 2020;382(8):727-733.
doi:10.1056/NEJMoa2001017
2. Zhou P, Yang XL, Wang XG, et al. A pneumonia
outbreak associated with a new coronavirus of
probable bat origin. Nature. 2020;579(7798):270273. doi:10.1038/s41586-020-2012-7
3. Zhao Y, Zhao Z, Wang Y, Zhou Y, Ma Y, Zuo W.
Single-cell RNA expression profiling of ACE2, the
putative receptor of Wuhan 2019-nCov. bioRxiv.
2020. doi:10.1101/2020.01.26.919985
4. World Health Organization. Coronavirus disease
2019 (COVID-19) situation report-45. Accessed
March 5, 2020. https://www.who.int/docs/defaultsource/coronaviruse/situation-reports/
20200305-sitrep-45-covid-19.pdf?sfvrsn=
ed2ba78b_2
5. Su S, Wong G, Shi W, et al. Epidemiology, genetic
recombination, and pathogenesis of coronaviruses.
Trends Microbiol. 2016;24(6):490-502. doi:10.1016/
j.tim.2016.03.003
6. World Health Organization. Middle East
respiratory syndrome coronavirus (MERS-CoV).
Published November 2019. Accessed January 19,
2020. https://www.who.int/emergencies/
mers-cov/en/
7. Guan WJ, Ni ZY, Hu Y, et al; China Medical
Treatment Expert Group for Covid-19. Clinical
characteristics of coronavirus disease 2019 in
China. N Engl J Med. 2020. doi:10.1056/
NEJMoa2002032
8. World Health Organization. Clinical management
of severe acute respiratory infection when Novel
coronavirus (nCoV) infection is suspected: interim
guidance. January 2020. Accessed February 5,
2020. https://www.who.int/internal-publicationsdetail/clinical-management-of-severe-acuterespiratory-infection-when-novel-coronavirus(ncov)-infection-is-suspected
9. Huang C, Wang Y, Li X, et al. Clinical features of
patients infected with 2019 novel coronavirus in
Wuhan, China. Lancet. 2020;395(10223):497-506.
doi:10.1016/S0140-6736(20)30183-5
10. Metlay JP, Waterer GW, Long AC, et al.
Diagnosis and treatment of adults with
community-acquired pneumonia: an official clinical
practice guideline of the American Thoracic Society
and Infectious Disease Society of America. Am J
Respir Crit Care Med. 2019;200(7):e45-e67. doi:10.
1164/rccm.201908-1581ST
11. Hamming I, Timens W, Bulthuis ML, Lely AT,
Navis G, van Goor H. Tissue distribution of ACE2
protein, the functional receptor for SARS
coronavirus: a first step in understanding SARS
pathogenesis. J Pathol. 2004;203(2):631-637.
doi:10.1002/path.1570
12. National Health Commission of the People′s
Republic of China. Diagnosis and treatment of the
novel coronavirus pneumonia (Trial version 7) [D].
Published 2020. Accessed March 3, 2020. http://
www.nhc.gov.cn/yzygj/s7653p/202003/
46c9294a7dfe4cef80dc7f5912eb1989/files/
ce3e6945832a438eaae415350a8ce964.pdf
13. Marc D, Dominique JF, Élodie B, et al. Human
Coronavirus: Respiratory Pathogens Revisited as
Infectious Neuroinvasive, Neurotropic, and
Neurovirulent Agents. CRC Press; 2013:93-122.
14. Arabi YM, Balkhy HH, Hayden FG, et al. Middle
East Respiratory Syndrome. N Engl J Med. 2017;376
(6):584-594. doi:10.1056/NEJMsr1408795
15. Cabello-Verrugio C, Morales MG, Rivera JC,
Cabrera D, Simon F. Renin-angiotensin system: an
old player with novel functions in skeletal muscle.
Med Res Rev. 2015;35(3):437-463. doi:10.1002/
med.21343
16. Ding Y, He L, Zhang Q, et al. Organ distribution
of severe acute respiratory syndrome (SARS)
associated coronavirus (SARS-CoV) in SARS
patients: implications for pathogenesis and virus
transmission pathways. J Pathol. 2004;203(2):622630. doi:10.1002/path.1560
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